Method of preparing steroids and products resulting therefrom



United States Patent 3,483,232 METHOD OF PREPARING STEROIDS AND PRODUCTS RESULTING THEREFROM John Paul Dusza, Nanuet, N.Y., Joseph Peter Joseph, Cliifside Park, N.J., and Seymour Bernstein, New City, N.Y., assignors to American Cyanamid Company, Stamford, Conn., a corporation of Maine No Drawing. Filed June 11, 1965, Ser. No. 463,376 Int. Cl. C07c 169/60, 169/20, 167/30 US. Cl. 260--397.1 11 Claims This invention relates to steroid compounds. More particularly, the invention relates to a novel method of preparing 3,3-alkoxy-A -steroids and to new compounds resulting from the said process.

The process of this invention can be illustrated as follows:

R R H30 H3O HO R0 trialkylorthoformate, acid conditions \1 0H H30 H30 I I HO RO I wherein R is selected from the group consisting of hydrogen; hydroxyl;

CzHs H3G\ CH2 /C2 /CH:.; 033 CE 3 CH (ll \CH2 CH C CH 0% CH3 H: CH (ff-040w! alkyl and 0 R is alkyl, R is selected from the group consisting of lower alkyl and ethynyl.

The process of this invention comprises converting 313- hydroxy-A -steroids (I) into the respective 3fi-alkoxy-A "ice steroids (III) thereof by reaction with a trialkylorthoformate. Compounds which can be so converted include, for example, cholesterol, stigmasterol, and the like. Further, the process comprises converting 35,17/3-dihydroxy- A -steroids of the androstene series (II) into the respective 3fl-alkoxy-A -18-nor-steroids (IV) by a like reaction with a trialkylorthoformate. Compounds useful as starting materials in this conversion include, for example, l7a-methylandrost-5-ene-3B,l7fi-diol and 17a ethynylandrost-5-ene-3 3,17B-diol. Starting materials for either type of conversion have been described in the prior art.

The starting compounds for the preparation of the steroids of structure III above are well known steroids of the following general structure:

HO R

a L H wherein R is a member of a group consisting of hydrogen, hydroxyl,

czHs 0E3 /CH2 /CE2 CH3 GE: GE 3 /CH3 ('3 CH: O (I) OH CH H3 CH3 CH GO-lower alkyl 0 II E O and (l30-1ower alkyl The starting compounds for the preparation of the steroids of structure IV above are likewise well-known steroids of the following general structure:

H O L lu or "fluoroboric" acid with stirring. The mixture can be heated gently for about 2 to minutes or may be left at room temperature for about ten or fifteen minutes. Generally, the reaction is substantially complete after 5 to minutes after the addition of the acid. Frequently the alkoxy-steroid precipitates from the solution and the product is collected by filtration. Where the end product does not precipitate readily, the solution can be neutralized with an acid acceptor such as pyridine. The neutralized reaction mixture is then poured into water and the product is collected by filtration as above. Purification of the end products, in general, may be achieved by recrystallization from appropriate solvents such as methanol. Where two -1iquid phases were encountered after terminating the reaction, methylene chloride is added and the organic layer is separated and dried with sodium sulfate. On evaporation, a solid residue is obtained which is recrystallized as above. It is generally convenient to carry out the reaction at approximately room temperature, but higher temperatures may be needed at times, as in the preparation of the longer chained steroid ethers.

The choice of the particular alkyl orthoformate employed in the reaction determines the nature of the substituent at (3-3. A wide variety of trialkylorthoformates have been found to be reactive, as for example, methyl, ethyl, n-butyl, iso-butyl, amyl, 2-ethyl-hexyl and stearyl.

The present process presents an unexpected and radical improvement in the preparation of 35-alkoxy-A -steroids because of its brevity of operation and high yields. The invention presents a process for the direct conversion of a 3fl-hydroxy-A -steroid into a 3,6-alkoxy-A -steroid. Conventional methods heretofore used for this conversion are based on a two-step process; first an initial conversion of the steroid into its corresponding 3,13-p-toluene sulfonate and second, the subsequent reaction of the 35-ptoluenesulfonate to form the 3i8-alkoxy steroid with resultant lower yields in rnultistep processes.

The 3 8-alkoxy-n -steroids of this invention are useful as agents for the lowering of body cholesterol, and therefore have utility as hypocholesteremic agents.

A reaction run with androst-S-ene-Bfl,17(3-diol as the starting compound yields a mixture of two new steroids. The reaction may be illustrated as follows:

0H H I ii 0H O--CH H3O L H36 L "H v --H H30 H30 1 The following reactions have been carried out using the new method to yield the following three new steroids:

"CECE Q inm tes i HaCO OH CH3 R30 L L "CECE "CECH HaC H3O a s )a H HO moo,

The following examples illustrate in detail the preparation of representative 3-p8-alkoxy-n -steroids of the present OH tc (CHaO )aCH invention.

EXAMPLE 1 Preparation of SB-methoxycholest-S-ene from cholest- 5-en-3;3-ol

A solution of the cholest-S-en-Sfi-ol (0.5 g.) in trimethylorthoformate (5 ml.) is'stirred at room temperature. The addition of 72% perchloric acid (0.3 ml.) causes an immediate reaction and precipitation. After stirring the suspension for about three minutes, the reaction mixture is poured into a saturated aqueous sodium bicarbonate solution and filtered. The dried precipitate is recrystallized from methanol and the yield of 3B- methoxycholest-S-ene is approximately 400 mg., melting point 83 84 C.-

EXAMPLES 2 to 10 Following the general procedure of Example 1 the following compounds were prepared:

Melting Example R R Point, C.

2 CH: s: /CH2 (LE2 /CH3 83-84 a CH 5H,

3 CH CH: CH3 CH2 CH2 CH3 88 OH CH2 OH em 4. CH CH-CHa CH3 CH2 CH2 CH3 76-77 C CH2 CH I CH3 5 (CH )zCHCH2 CH3 CH2 CH2 CH 111112 O CH: CH I CH3 6 C a(C 2)r7 E: /C H2 E2 s 59-61 CH CH CH l (5H3 C2H5 7 CH3 CH: CH (5H CH3 119-120 efi cfi c JH;

8 CHs(CH2)3 CH3 /CE[\ H /CH: 105-106 CH CH CH $113 9 CHgCHa H 72-73 10 CH3(CH3)4 H 57-58 EXAMPLE 1 starting Steroid, the mpound 3,8-methoxy-17,17-dimeth- Preparation of methyl EBB-methoxy-S-etienate Following the procedure of Example 1 and using methyl 3fl-hydroxy-5-etienate in place of cholest-S-ene- 3 3-01 the compound methyl 3B-me'thoxy-5-etienate, melting point 134-135 C. is recovered.

EXAMPLE 12 Preparation of methyl 3fl-methoxy-bisnorcholenate v I When the procedure of Example 1 is followed using methyl 3 3-hydroxy-S-bisnorcholenate as the starting steroid, the compound obtained is methyl 3fl-methoxy-5- bisnorcholenate, melting point 118120.5 C.

EXAMPLE 13 Preparation of 3,9-methoxy-5-androsten-176-01 and methoxy-S-androsten-17j3-ol-17-f0rmate EXAMPLE 14 Preparation of 3 fl-methoxy- 1 7, 17-dimethyl-18-norandrosta-5,13-diene Using the procedure substantially as described in EX- ample 1 with 17u-methyl-5-androstene-3/3,17p-dio1 as the yl-l8-norandrosta-5,13-diene is recovered, melting point 93-94 C.

EXAMPLE 15 Preparation of l7a-ethynyl-3fl-methoxy-HIS-methyl- 1 8-norandrosta-5 l 3-diene When a procedure substantially as in Example 1 is followed using 17a-ethynyl-5-androstene-3fi,17 3-diol, the

compound 17a ethylyl 33- methoxy 17/3 methyl 18- norandrosta-5,13-dien, melting point 91.092.5 C. is recovered.

EXAMPLE 16 Preparation of 3fl-ethoxy-17a-ethynyl-l7p-methyl-18- norandrosta-5,13-diene R CH;

and

wherein R is selected from the group consisting of hydrogen; hydroxyl;

CrHr 17 9-01 which comprises contactingandrOst-B-ene-BBJTB- ll CH; C-O-lower alkyl and C-O-lower alkyl 10 R is alkyl; R is ethynyl which comprises contacting wherein R and R are as defined above, with a trialkylorthoformate under aqueous acid conditions for a period up to 15 minutes and recovering said compound there from.

2. A method of preparing '3B-methoxycholest-S-ene which comprises contacting cholest-S-en-Bfi-oL with trimethylorthoformate in the presence of perchloric acid and recovering said compound therefrom.

3. A method of preparing methyl 3 fl-methoxy-S-etienate 3 which comprises contacting 3B hydroxy 5 etienate with tri'methylorthoformate in the presence of perchloric acid and recovering said compound therefrom.

4. A method of preparing methy1-3B-methoxy-bisnorcholenate which comprises contacting 3fi-hydroxy-5-bis- 40 norcholenate with trimethylorthoformate in the presence of perchloric acid and recovering said compound there- 5. A method of preparing 3B-methoxy-5-androstendie] with trimethylorthoformate inthe presence of perchloric acid and recovering said compound therefrom.

6. A method of preparing 3fi-methoxy-17,17-dimethy1- 18-norandrosta-5,13-diene which comprises contacting l7a-methy1-5 androstene-3,9,17 3-dio1 with trimethylorthoformate in the presence ofperchloric acid and recovering said compound therefrom.

7. A method of preparing 17u-ethyny1-3fi-methoxy-17,8- methyl-l8-norandrosta-5,13-diene which comprises contacting 17a-ethyn I S-andrQStene-Sfi,17fl-dio1 with trimethylorthoformate in the presence of perchloric acid and recovering said compound therefrom. a

8. A method of preparing 3/3-ethoxy-17u-ethyny1-17B- methyl-17-norandrosta-5,13-diene which comprises oontacting'17a-ethyny1-S-androstene-Iifi,17'fl-diol with trimethylorthoformate in the presence of perchloric acid and recovering said compound therefrom.

9. The compound 17a-ethyny1-3fi-methoxy-Uri-methyl- 18-norandrosta-5, 13 -diene.

10. The compound 3fi-ethoxy-17a-ethynyl-17fi-methyl- 18-norandrosta-5,13-diene.

11. The compound Sfi-octadecyl oxycholest-S-ene.

References Cited UNITED STATES PATENTS 1/ 1957 Schaltegger 260-3972 12/1968 Dusza 260-397.2

OTHER REFERENCES EL'BERT L. ROBERTS, Primary Examiner U.S. Cl. X.R. 

1. METHOD OF PREPARING STEROIDS OF THE FORMULAS. 